Transdermal delivery patch

ABSTRACT

A composition suitable for use in a transdermal delivery patch for administration of a biologically active compound, the composition comprising a phosphate compound of tocopherol and a polymer carrier.

This patent application is a continuation of U.S. patent applicationSer. No. 14/086,738, filed on Nov. 21, 2013, now abandoned, which is acontinuation of U.S. patent application Ser. No. 13/501,500, filed onApr. 12, 2012, now U.S. Pat. No. 8,652,511, which is a national stagefiling under 35 U.S.C. 371 of International Patent Application No.PCT/AU2011/000358, filed Mar. 30, 2011, which claims the benefit ofpriority to U.S. Provisional Patent Application No. 61/319,002, filed onMar. 30, 2010, and U.S. Provisional Patent Application No. 61/319,007,filed on Mar. 30, 2010, the disclosures of each of which areincorporated by reference herein in their entireties.

TECHNICAL FIELD

The present invention relates to a composition suitable for use in atransdermal delivery patch for administration of a biologically activecompound, and a transdermal delivery patch comprising the composition,or matrix layer.

BACKGROUND

In this specification where a document, act or item of knowledge isreferred to or discussed, this reference or discussion is not anadmission that the document, act or item of knowledge or any combinationthereof was at the priority date, publicly available, known to thepublic, part of common general knowledge; or known to be relevant to anattempt to solve any problem with which this specification is concerned.

Drug delivery is the method or process of administering a pharmaceuticalcompound to achieve a therapeutic effect in humans and animals.

Drug delivery technologies have been developed to improvebioavailability, safety, duration, onset or release, of thepharmaceutical compound.

When developing drug delivery technologies, problems likely to beencountered include compatibility of the drug delivery system and thepharmaceutical compound, maintaining an adequate and effective duration,potential for side effects, and meeting patient convenience andcompliance. As a consequence, many drug delivery technologies fall shortof desired improvements and requirements.

Accordingly, there is still a need for alternate delivery systems thateffectively deliver drugs and other biologically active compounds.

SUMMARY

The present invention relates to a composition suitable for use in atransdermal delivery patch for administration of a biologically activecompound, and a transdermal delivery patch comprising the composition,or matrix layer.

Accordingly, a first aspect of the present invention provides a matrixlayer for use in a transdermal delivery patch for administration of abiologically active compound, the matrix layer comprising a mixture of amono-tocopheryl phosphate compound and a di-tocopheryl phosphatecompound and a polymer carrier wherein the polymer carrier is present inan amount within the range of about 30% w/w to about 95% w/w.

The present invention also provides use of the composition, or matrixlayer, in a transdermal delivery patch for administration of abiologically active compound.

It has surprisingly been found that biologically active compounds can beeffectively administered using a transdermal delivery patch.

A second aspect of the present invention provides a transdermal deliverypatch for administration of a biologically active compound comprisingthe composition, or matrix layer. The composition, or matrix layer, maybe a solid or semi-solid layer. The transdermal delivery patch maycomprise further layers.

A third aspect of the present invention provides a method for preparinga transdermal delivery patch for administration of a biologically activecompound comprising the steps of:

(i) combining a polymer carrier and optional inert carrier componentswith a suitable solvent;

(ii) combining (i) with a dispersion comprising a biologically activecompound and a mixture of a mono-tocopheryl phosphate compound and adi-tocopheryl phosphate compound;

(iii) stirring (ii) until complete homogenisation is achieved;

(iv) placing the composition of (iii) in a suitable mould or casting thecomposition of (iii) on a surface;

(v) drying the composition under heat.

DETAILED DESCRIPTION

The present invention relates to a composition suitable for use in atransdermal delivery patch for administration of a biologically activecompound, the composition comprising a phosphate compound of tocopheroland a polymer carrier. The composition, or matrix layer, may form partof a transdermal delivery matrix patch. It has been surprisingly foundthat a transdermal delivery patch comprising this composition, or matrixlayer, can effectively administer biologically active compounds.

Tocopheryl Phosphate Compound

The composition, or matrix layer, comprises a mixture of amono-tocopheryl phosphate compound and a di-tocopheryl phosphatecompound.

Vitamin E exists in eight different forms, namely four tocopherols andfour tocotrienols. All feature a chroman ring, with a hydroxyl groupthat can donate a hydrogen atom to reduce free radicals and ahydrophobic side chain which allows for penetration into biologicalmembranes. Such derivatives of vitamin E may be classified as “hydroxychromans”. Both tocopherols and tocotrienols occur in alpha, beta, gammaand delta forms, determined by the number and location of methyl groupson the chroman ring. The tocotrienols differ from the analogoustocopherols by the presence of three double bonds in the hydrophobicside chain. The various forms of vitamin E are shown by Formula (I):

R₁ R₂ R₃ α-tocopherol CH₃ CH₃ CH₃ α-tocotrienol β-tocopherol CH₃ H CH₃β-tocotrienol γ-tocopherol H CH₃ CH₃ γ-tocotrienol δ-tocopherol H H CH₃δ-tocotrienol

In the present invention, tocopherol in any of the four forms may beused. The alpha form of tocopherol is preferred.

The term “phosphate compound” refers to phosphorylated tocopherol, wherea covalent bond is formed between an oxygen atom (typically originatingfrom a hydroxyl group) of the tocopherol compound and the phosphorousatom of a phosphate group (PO₄).

The phosphate compound may be a phosphate mono-ester, phosphatedi-ester, phosphate tri-ester, pyrophosphate mono-ester, pyrophosphatedi-ester, or a salt or derivative thereof, or a combination thereof. Thedi- and tri-esters may comprise the same tocopherol form or differenttocopherol forms.

The “salts” include metal salts such as alkali or alkaline earth metalsalts, for example sodium, magnesium, potassium and calcium salts.Sodium and potassium salts are preferred.

The “derivatives” include phosphate compounds where one or morephosphate protons are replaced by a substituent. Some non-limitingexamples of derivatives include phosphatidyl derivatives where aphosphate proton is substituted with an amino-alkyl group, sugarderivatives where a phosphate proton is substituted with a sugar such asglucose.

The term “amino-alkyl group” refers to a group comprising an amino(—NH₂) group and an alkyl group. The term “alkyl” refers to straightchain, branched chain or cyclic hydrocarbon groups having from 1 to 8carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, cyclohexyl, heptyl, andoctyl. Phosphatidyl choline derivatives are most preferred.

The mono-tocopheryl phosphate compound may be selected from the groupconsisting of mono-(tocopheryl)phosphate, mono-(tocopheryl)phosphatemonosodium salt, mono-(tocopheryl)phosphate disodium salt,mono-(tocopheryl)phosphate monopotassium salt andmono-(tocopheryl)phosphate dipotassium salt, and the di-tocopherylphosphate compound may be selected from the group consisting ofdi-(tocopheryl)phosphate, di-(tocopheryl)phosphate monosodium salt anddi-(tocopheryl)phosphate monopotassium salt. These phosphate compoundsmay be derived from the alpha, beta, gamma or delta form of tocopherol,or a combination thereof.

When a combination of a mono-phosphate ester and a di-phosphate ester,that is a mono-(tocopheryl)phosphate and di-(tocopheryl)phosphate (whichmay in some instances herein be referred to as tocopheryl phosphatemixture or simply “TPM”), the ratio (% w/w) is at least 2:1, within arange of about 4:1 to about 1:4, within a range of about 6:4 to about8:2. The ratio may be about 2:1, about 6:4, or about 8:2.

The mixture of the mono-tocopheryl phosphate compound and thedi-tocopheryl phosphate compound may be present in an amount within arange of about 0.01% w/w to about 10% w/w, within the range of about0.1% w/w to about 5% w/w, within the range of about 0.1% w/w to about 3%w/w, within the range of about 0.1% w/w to about 2% w/w, within therange of about 0.1% w/w to about 1% w/w or within the range of about0.1% w/w to about 0.5% w/w, of the total concentration of thecomposition, or matrix layer. In some embodiments, the mixture of themono-tocopheryl phosphate compound and the di-tocopheryl phosphatecompound may be present in an amount within a range of about 0.5% w/w toabout 1.5% w/w, or in an amount of about 0.1% w/w, of the totalconcentration of the composition, or matrix layer.

Polymer Carrier

The composition, or matrix layer, also comprises a polymer carrier.

The polymer carrier may comprise natural and synthetic polymers,co-polymers, or terpolymers.

Natural polymers include rubbers, elastomers, polysaccharides such ascellulose, natural resins such as shellac and amber.

Synthetic polymers include, for example, acrylates, polyacrylates,polyalkyl acrylates, polyamides, polyesters, polycarbonates, polyimides,polystyrenes, acrylonitrile butadiene styrene, polyacrylonitrile,polybutadiene, poly(butylene terephthalate), poly(ether sulphone),poly(ether)ketones, polyethylene, poly(ethylene glycol), poly(ethyleneterphthalate), polypropylene, polytetratfluroethylene,styrene-acrylonitrile resin, poly(trimethylene terephthalate),polyurethanes, polyvinyl butyral, polyvinylchlorides,polyvinylidenedifluoride, povidones, poly(vinyl pyrrolidone),polychloroprene, fluoroelastomers, chloro-sulphonated rubbers,hypromellose, polyolefine elastomer, polyacrylamide, chlorinatedpolyethylene, polyethersulphone, nylon, liquid crystal polymers,polyethylene terephthalate (PET), polyphenylsulphone,polypthalaminepolyvinyl alcohol derivatives, poly ethylene glycols,ethylene vinyl acetate, polymethyl methacrylate, cellulose derivativessuch as ethyl cellulose, hydroxyl propyl methyl cellulose, sugarderivatives (gums) including derivatives of sorbitol and mannitol,silicone oil and silicone oil derivatives, polysiloxanes includingamine-resistant polysiloxanes, and siloxanes.

Preferred polymer carriers suitable for use in the composition, ormatrix layer, of the present invention include acrylates, povidones andsiloxanes. Particularly preferred polymer carriers include polyvinylpyrrolidone (e.g. PVP K90, MW 360,000 Da), polysiloxanes, polyalkylacrylates (e.g. DuroTak) and polymethyl methacrylate (e.g. EudragitE100). In one embodiment, the polymer carrier is polyvinyl pyrrolidone.In an alternate embodiment, the polymer carrier is polymethylmethacrylate.

The polymer carrier used in the composition, or matrix layer, may havesufficient tackiness to enable the transdermal delivery patch to adhereto skin. For instance, amine-resistant polysiloxanes and combinationsthereof can be used in the composition, or matrix layer. A combinationof a polysiloxane of medium tack and a polysiloxane of high tack is usedwould be most suitable. The polysiloxanes may be synthesized from linearbifunctional and branched polyfunctional oligomers. It has been foundthat the ratio of both types of oligomers determines the physicalproperties of the polymers. More polyfunctional oligomers result in amore cross-linked polymer with a higher cohesion and a reduced tack,less polyfunctional oligomers result in a higher tack and a reducedcohesion. A high tack version should be tacky enough for the transdermaldelivery patch to adhere to the surface of skin. A medium tack version,on the other hand, may not be tacky at all but could be useful byproviding a softening effect to other components included in thecomposition, or matrix layer. To increase the adhesive power of thecomposition, or matrix layer, a silicone oil (e.g. dimethicone) could beadded.

The polymer carrier may be present in an amount within the range ofabout 30% w/w to about 95% w/w, within the range of about 30% w/w toabout 80% w/w, or within the range of about 55% w/w to about 65% w/w, ofthe total weight of the composition, or matrix layer.

The polymer carrier may also comprise inert carrier components, such asfor example, anti-tacking agents, tackifiers, and plasticizers toachieve appropriate softness, flexibility and “tackiness” for thepolymer carrier to enable the composition, or matrix layer, to adhere tothe surface of skin, and thus provide consistent delivery.

For polymers which are naturally “tacky” and may need anti-tackiness tohave an appropriate consistency, anti-tacking agents that are solid withno stickiness property (i.e. low ability to retain solvents upon drying)and that can be mixed well (i.e. do not crystallise upon drying) withthe polymer carrier may be suitable. The selection would be based on thepolymer-type. Many surfactants are suitable for use as an anti-tackingagent with a polymer carrier. A more specific example of an anti-tackingagent is succinic acid. In specific embodiments, the anti-tacking agentmay be present in an amount or less than 1% w/w, up to about 1% w/w, orup to about 5% w/w, of the total weight of the composition, or matrixlayer.

In order to enhance the ability of the composition, or matrix layer, toadhere to the surface of skin, it may optionally contain a tackifier (ortacking agent). Tack can be controlled by combining adhesives of varyinghardnesses (glass temperature or TO. Typically, a tackifier is a polymerwhich is insoluble in water and composed of a monomer which containspartly or wholly a (meth)acrylic alkyl ester. Such types of polymersinclude, but are not limited to, acrylic, N-butyl-methacrylic copolymer(Primal N580NF, sold by Japan Acrylic Chemical Company, Ltd.), acrylicmethyl, acrylic 2-ethylhexyl copolymer (Nikasol TS-6520, sold by NipponCarbide Industries Company, Ltd), polyacrylic acid (Jurymer AC-IOLPH,sold by Nihon Junyaku Company, Ltd), methacrylic copolymer L (PlastoidL50, sold by Rohm Pharma GmbH), and aminoalkylmethacrylate copolymer E(Plastoid E35L, Plastoid E35M, Plastoid E35H, all sold by Rohm PharmaGmbH). Other non-limiting examples include rosin esters, hydrogenatedrosins, dipropylene glycol dibenzoate, and/or mixed hydrocarbons, andacrylic copolymers (e.g. Flexbond 150 adhesive by Air Products).

Plasticizers are additives that increase the plasticity or fluidity ofthe material to which they are added. Plasticizers may be used in thepresent invention to soften the final product increasing its flexibilityand making it less brittle. Suitable plasticizers include phthalates,esters of polycarboxylic acids with linear or branched aliphaticalcohols of moderate chain length, acetylated monoglycerides, alkylcitrates, triethyl citrate (TEC), acetyl triethyl citrate (ATEC),tributyl citrate (TBC), acetyl tributyl citrate (ATBC), trioctyl citrate(TOC), acetyl trioctyl citrate (ATOC), trihexyl citrate (THC), acetyltrihexyl citrate (ATHC), butyryl trihexyl citrate (BTHC, trihexylo-butyryl citrate), trimethyl citrate (TMC), methyl laurate, lauricacid, lauryl lactate, lauryl alcohol, alkyl sulphonic acid phenyl ester,diethylene glycol monoethyl ether, bis(2-ethylhexyl) phthalate (DEHP),diisooctyl phthalate (DIOP), bis(n-butyl)phthalate (DnBP, DBP),diisobutyl phthalate (DIBP), bis(2-ethylhexyl)adipate (DEHA), dimethyladipate (DMAD), monomethyl adipate (MMAD), dioctyl adipate (DOA), ethyloleate, sorbitan monooleate, glycerol monooleate, dibutyl sebacate(DBS), dibutyl maleate (DBM), diisobutyl maleate (DIBM), benzoates,epoxidized vegetable oils, tris(tromethamine), N-ethyl toluenesulfonamide (o/p ETSA), N-(2-hydroxypropyl)benzene sulfonamide (HP BSA),N-(n-butyl)benzene sulfonamide (BBSA-NBBS), tricresyl phosphate (TCP),tributyl phosphate (TBP), triethylene glycol dihexanoate (3G6, 3GH),tetraethylene glycol diheptanoate (4G7), 1,3-butyleneglycol, dipropyleneglycol, PEG400, Span 80, and polyvinylpyrrolidone. Dibutyl sebacate(DBS), sorbitan monooleate, methyl laurate and lauric acid are preferredplasticizers.

Inert carrier components may be present in an amount within the range ofabout 0.001% w/w to about 50% w/w, within the range of about 0.001% w/wto about 40% w/w, within the range of about 0.001% w/w to about 30% w/w,of the total weight of the composition, or matrix layer. In oneembodiment, the composition, or matrix layer comprises an anti-tackingagent (such as succinic acid) and a plasticizer (such as dibutylsebacate) in a total amount of about 35% w/w of the total weight of thecomposition, or matrix layer.

The amount of polymer carrier and optional inert carrier componentspresent in the composition, or matrix layer will depend on the specificbiologically active compound to be administered. Generally, however,these components may be present in an amount within the range of about50% w/w to about 99% w/w, within the range of about 80% w/w to about 98%w/w, within the range of about 90% w/w to about 98% w/w, of the totalweight of the composition, or matrix layer. In one embodiment, thecomposition, or matrix layer, comprises these components in the amountof about 95% w/w of the total weight of the composition, or matrixlayer.

It should be noted that, in some instances herein, the term “polymercarrier” could be used collectively to refer to the polymer carrier andthe inert carrier components.

The composition, or matrix layer, may also optionally further compriseone or more excipients (in addition to the inert carrier componentsdiscussed above).

A person skilled in the art of the invention would appreciate what aresuitable excipients for inclusion in the composition, or matrix layer,of the invention. Some examples include, but are not limited to,solvents, thickeners or gelling agents, preservatives, surfactants,stabilizers, buffers, emollients, colours, fragrances, and appearancemodifiers. It will be appreciated that any excipients which have beenapproved for use in pharmaceutical products by the regulatory bodies maybe employed in the composition, or matrix layer, of the presentinvention. The amount of a particular excipient or excipients to be usedin a composition, or matrix layer, of the present invention would alsobe appreciated by a person skilled in the art.

Biologically Active Compounds

The composition, or matrix layer, may form part of a transdermaldelivery matrix patch. It has been surprisingly found that a transdermaldelivery patch comprising this composition, or matrix layer, caneffectively administer biologically active compounds.

The term “biologically active compound” refers to any chemical substancethat has a biological effect in humans or animals for medical,therapeutic, cosmetic and veterinary purposes, and encompassespharmaceuticals including drugs, cosmeceuticals, nutraceuticals, andnutritional agents. It will be appreciated that some of biologicallyactive compounds can be classified in more than one of these classes.

A wide range of biologically active compounds may be delivered with thetransdermal delivery patch of the present invention. Examples include,but are not limited to, cardiovascular drugs, in particularantihypertensive agents (e.g. calcium channel blockers or calciumantagonists) and antiarrhythmic agents; congestive heart-failurepharmaceuticals; inotropic agents; vasodilators; ACE inhibitors;diuretics; carbonic anhydrase inhibitors; cardiac glycosides;phosphodiesterase inhibitors; α blockers; β-blockers; sodium channelblockers; potassium channel blockers; β-adrenergic agonists; plateletinhibitors; angiotensin II antagonists; anticoagulants; thrombolyticagents; treatments for bleeding; treatments for anaemia; thrombininhibitors; antiparasitic agents; antibacterial agents; insulin; humangrowth hormone and peptides; vaccines; antiinflammatory agents, inparticular non-steroidal antiinflammatory agents (NSAIDs), moreparticularly COX-2 inhibitors; steroidal antiinflammatory agents;prophylactic antiinflammatory agents; antiglaucoma agents; mast cellstabilisers; mydriatics; agents affecting the respiratory system;allergic rhinitis pharmaceuticals; alpha-adrenergic agonists;corticosteroids; chronic obstructive pulmonary disease pharmaceuticals;xanthine-oxidase inhibitors; antiarthritis agents; gout treatments;autacoids and autacoid antagonists; antimycobacterial agents; antifungalagents; antiprotozoal agents; anthelmintic agents; antiviral agentsespecially for respiratory, herpes, cyto-megalovirus, humanimmunodeficiency virus and hepatitis infections; treatments for leukemiaand kaposi's sarcoma; pain management agents in particular opioids,anaesthetics and analgesics; neuroleptics; sympathomimeticpharmaceuticals; adrenergic agonists; drugs affecting neurotransmitteruptake or release; anticholinergic pharmaceuticals; antihaemorrhoidtreatments; agents to prevent or treat radiation or chemotherapeuticeffects; liopgenisis drugs; fat reducing treatments; anti-obesitypeptides; antiobesity agents such as lipase inhibitors; sympathomimeticagents; treatments for gastric ulcers and inflammation such as protonpump inhibitors; prostaglandins; VEGF inhibitors; antihyperlipidemicagents, in particular statins; drugs that affect the central nervoussystem (CNS) such as antipsychotic, antiepileptic and antiseizure drugs(anticonvulsants), psychoactive drugs, stimulants, antianxiety andhypnotic drugs, antidepressant drugs; antiparkinson's pharmaceuticals;hormones and fragments thereof such as sex hormones; growth hormoneantagonists; gonadotropin releasing hormones and analogues thereof;steroid hormones and their antagonists; selective estrogen modulators;growth factors; antidiabetic pharmaceuticals such as insulin, insulinfragments, insulin analogues, glucagon-like peptides and hypoglycaemicagents; H1, H2, H3 and H4 antihistamines; peptide, protein, polypeptide,nucleic acids and oligonucleotide pharmaceuticals; analogues, fragmentsand varients of natural proteins, polypeptides, oligonucleaotides andnucleic acids and such like compounds; agents used to treat migraineheadaches; asthma pharmaceuticals; cholinergic antagonists;glucocorticoids; androgens; antiandrogens; inhibitors of adrenocorticoidbiosynthesis; osteoporosis treatments such as biphosphonates;antithyroid pharmaceuticals; suncreens, sun protectants and filters;cytokine agonists; cytokine antagonists; anticancer drugs; antialzheimerdrugs; HMGCoA reductase inhibitors; fibrates; cholesterol absorptioninhibitors; HDL cholesterol elevating agents; triglyceride reducingagents; antiageing or antiwrinkle agents; precursor molcules for thegeneration of hormones; proteins such as collagen and elastin;antibacterial agents; anti acne agents; antioxidants; hair treatmentsand skin whitening agents; suncreens, sun protectants and filters;variants of human apolipoprotein; precursor molecules for generation ofhormones; proteins and peptides thereof; amino acids; plant extractssuch as grape seed extract; DHEA; isoflavones; nutritional agentsincluding vitamins, phytosterols and iridoid gylcosides, sesquiterpenelactones, terpenes, phenolic glycosides, triterpenes, hydroquinonederivatives, phenylalkanones; antioxidants such as retinol and otherretinoids including retinoic acid and co enzyme Q10; omega-3-fattyacids; glucosamine; nucleic acids, oligonucleotides, antisensepharmaceuticals; enzymes; cytokines; cytokine analogues; cytokineagonists; cytokine antagonists; immunoglobulins; antibodies; antibodypharmaceuticals; gene therapies; lipoproteins; erythropoietin; vaccines;small and large molecule therapeutic agents for the treatment, orprevention of human and animal diseases such as allergy/asthma,arthritis, cancer, diabetes, growth impairment, cardiovascular diseases,inflammation, immunological disorders, baldness, pain, ophthalmologicaldiseases, epilepsy, gynaecological disorders, CNS diseases, viralinfections, bacterial infections, parasitic infections, GI diseases,obesity, and haemological diseases.

Some specific non-limiting examples of suitable biologically activecompounds include:

Anaesthetics:

including amino-ester and amino-amide anaesthetics such as benzocaine,chloroprocaine, cocaine, reserpine, guanethidine, cyclomethycaine,dimethocaine/larocaine, propoxycaine, procaine/novocaine, proparacaine,tetracaine/amethocaine; articaine, bupivacaine, carticaine,cinchocaine/dibucaine, etidocaine, levobupivacaine,lidocaine/lignocaine, mepivacaine, piperocaine, prilocaine, ropivacaine,trimecaine, propofol, halothane, enflurane barbiturates,benzodiazepines, neostigmine and ketamine

Alkylating Agents:

including carmustine, cyclophosphamide, ifosfamide, streptozotocin andmechlorethamine

Calcium Channel Blockers:

including amlodipine, aranidipine, azelnidipine, barnidipine,benidipine, cilnidipine, clevidipine, cronidipine, darodipine,dexniguldipine, efonidipine, elnadipine, elgodipine, felodipine,flordipine, furnidipine, iganidipine, isradipine, lacidipine,lemildipine, lercanidipine, manidipine, mesuldipine, nicardipine,nifedipine, niludipine, nilvadipine, nimodipine, nisoldipine,nitrendipine, olradipine, oxodipine, palonidipine, pranidipine,sagandipine, sornidipine, teludipine, tiamdipine, trombodipine,watanidipine, verapamil, gallopamil, benzothiazepine, diltiazem,mibefradil, bepridil, fluspirilene and fendiline

Antiarrhythmic and Antiangina Agents:

including amiodarone, disopyramide, flecainide acetate, quinidinesulphate, nitroglycerine, ranolazine, amiodarone, isosorbide andalteplase

Antibacterial, Antibiotic and Antiacne Agents:

including amoxicillin, ampicillin, azithromycin, benethamine penicillin,bleomycin, benzoyl peroxide, cinoxacin, chloramphenicol, daunorubicin,plicamycin, fluoroquinolones, ciprofloxacin, clarithromycin,clindamycin, clindesse, clofazimine, chlorohexidine gluconate,cloxacillin, demeclocycline, doxycycline, erythromycin, ethionamide,imipenem, indomethacin, lymocycline, minocycline, nalidixic acid,nitrofurantoin, penicillin, rifampicin, spiramycin, sodiumsulfacetamide, sulphabenzamide, sulphadoxine, sulphamerazine,sulphacetamide, sulphadiazine, sulphafurazole, sulphamethoxazole,sulphapyridine, tetracycline, cephalexin, cefdinir, triclosan,ofloxacin, vancocin, glyburide, mupirocin, cefprozil, cefuroxime axetil,norfloxacin, isoniazid, lupulone, D-penicillamine, levofloxacin,gatifoxacin, and trimethoprim

Anticancer:

including doxorubicin, 6-thioguanine, paclitaxel, docetaxel,camptothecin, megestrol acetate, navelbine, cytarabine, fludarabine,6-mercaptopurine, 5-fluorouracil, teniposide, vinblastine, vincristine,cisplatin, colchicine, carboplatin, procarbazine and etopside

Antidepressants, Antipsychotics and Antianxiety:

including alprazolam, amoxapine, bentazepam, bromazepam, clorazipine,clobazam, clotiazepam, diazepam, lorazepam, flunitrazepam, flurazepam,lormetazepam, medazepam, nitrazepam, oxazepam, temazepam, maprotiline,mianserin, nortriptyline, risperidone, sertraline, trazodone,baloperidol, trimipramine maleate fluoxetine, ondansetron, midazolam,chlorpromazine, haloperidol, triazolam, clozapine, fluopromazine,fluphenazine decanoate, fluanisone, perphenazine, pimozide,prochlorperazine, sulpiride, thioridazine, paroxitine, citalopram,bupropion, phenelzine, olanzapine, divalproex sodium and venlafaxine

Tricyclics:

including azothiopine, amitriptyline, famotidine, promethazine,paroxatine, oxcarbazapine and mertazapine

Antidiabetics:

including acetohexamide, chlorpropamide, glibenclaraide, gliclazide,glipizide, metformin, tolazamide, glyburide, glimepiride and tolbutamide

Antiepileptics:

including beclamide, carbamazepine, gapapentin, tiagabine, vigabatrin,topiramate, clonazepam, ethotoin, methoin, methsuximide,methylphenobarbitone, oxcarbazepine, paramethadione, phenacemide,phenobarbitone, phenyloin, phensuximide, primidone, sulthiamine,phenytoin sodium, nirofurantoin monohydrate, gabapentin, lamotrigine,zonisamide, ethosuximide and valproic acid

Hypnotics/Sedatives and Muscle Relaxants:

including zolpidem tartrate, amylobarbitone, barbitone, butobarbitone,pentobarbitone, brotizolam, carbromal, chlordiazepoxide,chlormethiazole, ethinamate, meprobamate, methaqualome, cyclobenzaprene,cyclobenzaprine, tizanidine, baclofen, butalbital, zopiclone,atracurium, tubocurarine and Phenobarbital

Antifungal, Antiprotazoal and Antiparasitic Agents:

including amphotericin, butoconazole nitrate, clotrimazole, econazolenitrate, fluconazole, flucytosine, griseofulvin, itraconazole,ketoconazole, miconazole, natamycin, nystatin, sulconazole nitrate,terconazole, tioconazole and undecenoic acid; benznidazole, clioquinol,decoquinate, diiodohydroxyquinoline, diloxanide furoate, dinitolmide,furzolidone, metronidazole, nimorazole, nitrofurazone, ornidazole,terbinafine, clotrimazole, chloroquine, mefloquine, itraconazole,pyrimethamine, praziquantel, quinacrine, mebendazole and tinidazole

Antihypertensive and Cardiac Therapeutic Agents:

including candesartan, hydralazine, clonidine, triamterene, felodipine,gemfibrozil, fenofibrate, nifedical, prazosin, mecamylamine, doxazosin,dobutamine and cilexetil

Antimigraine Agents:

including dihydroergotamine mesylate, ergotamine tartrate, methysergidemaleate, pizotifen maleate and sumatriptan succinate

Antimuscarinic Agents:

including atropine, benzhexol, biperiden, ethopropazine, hyoscyamine,mepenzolate bromide, oxybutynin, oxyphencylcimine and tropicamide

Antineoplastic Agents (or Immunosuppressants):

including aminoglutethimide, amsacrine, azathioprine, busulphan,chlorambucil, cyclosporin, dacarbazine, estramustine, etoposide,lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane,mitozantrone, procarbazine, tamoxifen citrate, testolactone, tacrolimus,mercaptopurine and sirolimus

Antiparkinsonian Agents:

including bromocriptine mesylate, levodopa, tolcapone, ropinirole,bromocriptine, hypoglycaemic agents such as sulfonylureas, biguanides,α-glucosidase inhibitors, thaiazolidinediones, cabergoline, carbidopaand lysuride maleate

Antithyroid Agents:

including carbimazole and propylthiouracil

Antiviral Drugs:

including amantadine, retinovir, cidofovir, acyclovir, famciclovir,ribavirin, amprenavir, indinavirm, rimantadine and efavirenz,penciclovir, ganciclovir, vidarabine, abacavir, adefovir, apmrenavir,delavirdine, didanosine, stavudine, zalcitabine, zidovudine, enfuvirtideand interferon

Cardiac Inotropic Agents:

including amrinone, milrinone, digitoxin, digoxin, enoximone, lanatosideC and medigoxin

Hypo and Hyper Lipidemic Agents:

including fenofibrate, clofibrate, probucol, ezetimibe and torcetrapib

Antiinflammatory:

including meoxicam, triamcinolone, cromolyn, nedocromil,hydroxychloroquine, montelukast, zileuton, zafirlukast and meloxicam

Antihistamine:

including fexofenadine, chloral hydrate, hydroxyzine, promethazine,cetirazine, cimetidine, clyclizine, meclizine, dimenhydrinate,loratadine, nizatadine and promethazine

Antiulcer:

including omeprazole, lansoprazole, pantoprazole and ranitidine

Diuretics:

including hydrochlorothiazide, amiloride, acetazolamide, furosemide andtorsemide

Opioids:

including natural opiates which are alkaloids contained in the resin ofthe opium poppy such as morphine, codeine and thebaine; semi-syntheticopioids created from natural opiates such as hydromorphone, hydrocodone,oxycodone, oxymorphone, desomorphine, diacetylmorphine (heroin),nicomorphine, dipropanoylmorphine, benzylmorphine and ethylmorphine;fully synthetic opioids such as fentanyl, pethidine, methadone, tramadoland dextropropoxyphene; and, endogenous opioid peptides, producednaturally in the body, such as endorphins, enkephalins, dynorphins, andendomorphins; opioid analgesics including opioid receptor agonists,opioid receptor partial agonists, opioid antagonist or opioid receptormixed agonist-antagonists; opioid receptor agonists including morphine,depomorphine, etorphine, heroin, hydromorphone, oxymorphone,levorphanol, methadone, levomethadyl, meperidine, fentanyl, sufentanyl,alfentanil, codeine, hydrocodone, oxycodone, and mixtures of theforegoing; opioid receptor antagonists including naloxone andnaltrexone; opioid receptor mixed agonist-antagonist which has mixedopioid agonist/antagonist activities, or one that exhibits only partialagonist activity, including buprenorphine, nalbuphine, butorphanol,pentazocine, and mixtures of such compounds; opioids which exhibitpartial agonist activity, including ethylketocyclazocine; opiumalkaloids including phenanthrenes which are naturally occurring in opiumsuch as codeine, morphine, thebaine and oripavine (the active metaboliteof thebaine); synthetic derivatives such as diacetylmorphine (heroin),dihydrocodeine, hydrocodone, hydromorphone, nicomorphine, desmorphine,ethylmorphine, dipropanoylmorphine, oxycodone and oxymorphone; syntheticopioids including anilidopiperidines such as fentanyl,alphamethylfentanyl, alfentanil, sufentanil, remifentanil, carfentanyland ohmefentanyl, Phenylpiperidines such as pethidine (meperidine),ketobemidone, MPPP, allylprodine, prodine and PEPAP; diphenylpropylaminederivatives such as propoxyphene, dextropropoxyphene, dextromoramide,bezitramide, piritramide, methadone, dipipanone, levomethadyl acetate(LAAM), difenoxin, diphenoxylate and loperamide; benzomorphanderivatives such as dezocine, pentazocine and phenazocine; oripavinederivatives such as buprenorphine, dihydroetorphine and etorphine;morphinan derivatives such as butorphanol, nalbuphine, levorphanol andlevomethorphan, and others such as lefetamine, meptazinol, tilidine,tramadol and tapentadol; opioid receptor antagonists includingnalmefene, naloxone and naltrexone

NSAIDs:

including arylalkanoic acid sub-group of class which includesdiclofenac, aceclofenac, acemetacin, alclofenac, bromfenac, etodolac,indometacin, indometacin farnesil, nabumetone, oxametacin,proglumetacin, sulindac and tolmetin; 2-arylpropionic acid (profens)sub-group of class which includes alminoprofen, benoxaprofen, carprofen,dexibuprofen, dexketoprofen, fenbufen, fenoprofen, flunoxaprofen,flurbiprofen, ibuprofen, ibuproxam, indoprofen, ketoprofen, ketorolac,loxoprofen, miroprofen, naproxen, oxaprozin, pirprofen, suprofen,tarenflurbil and tiaprofenic acid; and N-arylanthranilic acid (fenamicacid) sub-group of class which includes flufenamic acid, meclofenamicacid, mefenamic acid and tolfenamic acid; tromethamine, celecoxib,nepafenac, aspirin, rofecoxib, naproxen, sulindac, piroxicam,pheylbutazone, tolmetin, indomethacin, acetominophen (paracetamol),tramadol and propoxyphene

Retinoids:

including first generation retinoids such as retinol, retinal, tretinoin(retinoic acid, Retin-A), isotretinoin and alitertinoin; secondgeneration retinoids such as etretinate and its metabolite acitretin;third generation retinoids such as tazarotene, bexarotene and adapalene

Hormones and Steroids:

including adrenocorticotrophic hormone (ACTH), antidiruetic hormone(vasopressin), atrial-nartreuretic factor (ANF), atrial-nartreureticpeptide (ANP), beclomethasone, cortisone, scopolamine, dopamine,epinephrine, catecholamines, cholecystokinin, clomiphene citrate,danazol, dexamethasone, diethylstilbestrol (DES), ethinyl estradiol,fludrocortison, finasteride, follicle stimulating hormone, gastrin,hydroxyprogesterone, growth hormone, insulin, leptin, luteinizinghormone, medroxyprogesterone acetate, mestranol, quinestrol,methyltestosterone, nandrolone, norethindrone, norethisterone,norgestrel, estradiol, conjugated oestrogens, oxandrolone, oxytocin,prednisone, progesterone, prolactin, protogalndins, somatostatin,stanozolol, stibestrol, thyroxine, prednisolone phosphate,triamcinolone, mifepristone acetonide, budesonide, levothyroxine,testosterone, testosterone cypionate, fluoxymesterone, flutamide,mometasone furoate, cyproterone, fluromethalone, goserelin, leuprolide,calcitonin, halobetasol, hydrocortisol and tibolone

Statins and Derivatives:

including atorvastatin, fluvastatin, lovastatin, nystatin, rosuvastatin,pravastatin, orlistat and simvastatin

Stimulants:

including amphetamine, phentermine, tyramine, ephedrine, metaraminol,phenylephrine, dexamphetamine, dexfenfluramine, fenfluramine, nicotine,caffeine and mazindol

Vasocontrictors:

including desmopressin

Vasodilitors:

including carvedilol, terazosin, phentolamine and menthol

Antialzheimers:

including levetiracetam, levitiracetam and donepezil

ACE Inhibitors:

including benzapril, enalapril, ramipril, fosinopril sodium, lisinopril,minoxidil, isosorbide, rampril and quinapril

Beta Adrenoreceptor Antogonists:

including atenolol, timolol, pindolol, propanolol hydrochloride,bisoprolol, esmolol, metoprolol succinate, metoprolol and metoprololtartrate

Angiotensin II Antagonists:

including losartan

Platelet Inhibitors:

including abciximab, clopidrogel, tirofiban and aspirin

Alcohols and Phenols:

including tramadol, tramadol hydrochloride, allopurinol, calcitriol,cilostazol, soltalol, urasodiol bromperidol, droperidol, flupenthixoldecanoate, albuterol, albuterol sulphate, carisoprodol, chlobetasol,ropinirol, labetalol, and methocarbamol

Ketones and Esters:

including amioderone, fluticasone, spironolactone, prednisone,triazodone, desoximetasone, methyl prednisdone, benzonatate nabumetoneand buspirone

Antiemetics:

including metoclopramide

Ocular Treatments:

including dorzolamide, brimonidine, olopatadine, cyclopentolate,pilocarpine and echothiophate

Anticoagulant and Antithrombitic Agents:

including warfarin, enoxaparin and lepirudin

Treatments for Gout:

including probenecid and sulfinpyrazone

COPD and Asthma Treatments:

including ipratropium

Treatments for Osteoporosis:

including raloxifene, pamidronate and risedronate

Cosmetic Peptides:

including acetyl hexapeptide-3, acetyl hexapeptide-8, acetyl octapeptideand 1-carnosine

Vaccines:

including vaccines comprising toxoids (inactivated toxic compounds);proteins, protein subunits and polypeptides; polynucleotides such as DNAand RNA; conjugates; adjuvants such as saponins, virosomes, inorganicand organic adjuvants, for example zostavax

Nutraceutical and Cosmeceutical Actives:

including coenzyme Q₁₀ (or ubiquinone), ubiquinol or resveratrol; acarotenoid such as α, β, or γ-carotene, lycopene, lutein, zeaxanthin andastaxanthin; a phytonutrient, such as lycopene, lutein and seaxanthin;an unsaturated fatty acid such as linoleic acid, conjugated linoleicacid, linolenic acid, omega-3 fatty acids including but not limited todocosahexaenoic acid (DHA) and eicosapentaeonic acid (EPA) and theirglycerol-esters; fat-soluble vitamins including vitamin D (D2, D3 andtheir derivatives), vitamin E (α, β, γ, δ-tocopherols, or α, β, γ,δ-tocotrienols), vitamin A (retinol, retinal, retinoic acid andderivatives), vitamin K (K₁, K₂, K₃ and their derivatives)capric/caprylic triglycerides, folic acid, iron, niacin, glyceryllinoleate, omega 6 fatty acids, vitamin F, selenium, cyanocobalamin,aloe vera, beta glucan, bisabolol, camellia thea (green tea) extract,capric/caprylic triglycerides, centella asiatica (gotu cola) extract,cetearyl olivate, chlorophyll, citrus sinensis (orange) oil, cocoylproline, dicapryl ether, disodium lauriminodipropionate tocopherylphosphates (vitamin E phosphates), glycerin, glyceryl oleate,glycyrrhiza glabra (licorice) root extract, hamamelis virgiana (witchhazel) extract, lactic acid, lecithin, lutein, macadamia integrifolia(macadamia) seed oil, matricaria chamomilla (chamomile) extract,oenothera biennis (evening primrose) oil, olea europaea (olive) leafextract, rice bran oil, persea gratissima (avocado) oil, polygonummultiflorum extract, pomegranate sterols, resveratrol, rosa eglanteria(rose hip) oil, santalum spicatum (sandalwood) oil, titanium dioxide,folic acid, glycerin, glyceryl linoleate (omega 6 fatty acids vitaminF), vitamin A palmitate, vitis vinifera (grapeseed) oil, halobetasol,adenosine, adenosine triphosphate, alpha hydroxy acid, allantoin,hyaluronic acid and derivatives, isolutrol, tranexamic acid, glycolicacid, arginine, ascorbyl glucosamine, ascorbyl palmitate, salicylicacid, carnosic acid, alpha lipoic acid, gamma linolenic acid (GLA),panthenol, retinyl propionate, retinyl pamitate, furfuryladenine,retinaldehyde, copper pepetides, idebenone, dimethylaminoethanol (DMAE),niacinamide, beta-glucan, palmitoyl pentapeptide-4, palmitoyloligopeptide/tetrapetide-7, ethocyn, ceramides, phenylalanine,glucuronolactone, L-carnitine, hydroxylapetite, palmitoyl tripetide-3,forskolin, zinc oxide, α-bisabolol, eugenol, silybin, soy isoflavones,aucubin, catalpol, pseudoguaianolide from Arnica chamissonis, rosmarinicacid, rosmanol, salicylates for example salicin, saligenin andsalicyclic acid, taxasterol, α-lactucerol, isolactucerol, taraxacoside,ceremides, arbutin, gingerols, shagaols, hypercin, elastin, collagen andpeptides thereof.

Particularly preferred biologically active compounds include alprazolam,donepazil, rispiredone, lorazepam, nicotine, lidocaine, diclofenac,felodipine, insulin, ketoralac, prilocaine, halobetasol, hydrocortisol,opioids such as oxycodone or dihydrohydroxycodeinone (oxycodone base).

It is to be understood that pharmaceutically, nutraceutically orcosmeceutically acceptable derivatives of biologically active compoundsare included within the scope of the present invention.

The term “pharmaceutically, nutraceutically or cosmeceuticallyacceptable derivatives” includes, but is not limited to,pharmaceutically, nutraceutically or cosmeceutically acceptable salts,esters, salts of such esters, ethers, or any other derivative includingprodrugs and metabolites, which upon administration to a subject (e.g.patient, human or animal) in need is capable of providing, directly orindirectly, a biologically active compound as otherwise describedherein.

As used herein, the term “pharmaceutically, nutraceutically orcosmeceutically acceptable salt” refers to those salts which are, withinthe scope of sound medical judgment, suitable for use in contact withthe tissues of humans and lower animals without undue toxicity,irritation, allergic response and the like, and are commensurate with areasonable benefit/risk ratio. Pharmaceutically, nutraceutically orcosmeceutically acceptable salts are well known in the art. For example,S. M. Berge, et al. describe pharmaceutically, nutraceutically orcosmeceutically acceptable salts in detail in J. PharmaceuticalSciences, 66:1-19, 1977. Examples of pharmaceutically, nutraceuticallyor cosmeceutically acceptable nontoxic acid addition salts are salts ofan amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, oxalic acid, maleic acid,tartaric acid, citric acid, succinic acid, or malonic acid or by usingother methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hernisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like.Further pharmaceutically acceptable salts include, when appropriate,nontoxic ammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate, and aryl sulfonate.

The term “pharmaceutically, nutraceutically or cosmeceuticallyacceptable ester” refers to esters which are hydrolysed in vivo andinclude those that break down readily in the human body to leave theparent compound or a salt thereof. Suitable ester groups include, forexample, those derived from pharmaceutically, nutraceutically orcosmeceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters include formates, acetates, propionates,butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically, nutraceutically or cosmeceuticallyacceptable prodrugs” as used herein refers to those prodrugs of thebiologically active compounds which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues of asubject with undue toxicity, irritation, allergic response, and thelike, commensurate with a reasonable benefit/risk ratio, and effectivefor their intended use, as well as the zwitterionic forms, wherepossible, of the compounds of the invention. The term “prodrug” refersto compounds that are rapidly transformed in vivo to yield the parentcompound of the above formula, for example by hydrolysis in blood. Athorough discussion is provided in T. Higuchi and V. Stella, Pro-drugsas Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, andin Edward B. Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987.

The present invention is further not limited solely to theadministration of one biologically active compound: more than onebiologically active compound or other therapeutic compounds may beincorporated into the composition, or matrix layer.

The biologically active compound may be present in a therapeuticallyeffective amount, that is, an amount necessary to achieve a desiredtherapeutic effect. Typically, the biologically active compound will bepresent in an amount within the range of about 0.1% w/w to about 30%w/w, within the range of about 0.1% w/w to about 20% w/w, within therange of about 0.1% w/w to about 10% w/w, of the total concentration ofthe composition, or matrix layer. In one embodiment, the matrix layerwill have a biologically active compound concentration within the rangeof about 3.0% w/w to about 15.0% w/w of the total concentration of thecomposition, or matrix layer.

The ratio of biologically active compound:TP (% w/w) may be within therange of about 5:5 to about 5:0.5, with the most preferred valuepreferably being about 5:1. The polymer carrier:[biologically activecompound and TP] may be within the range of about 1:1 to about 3:1, withpreferred values preferably being within the range of about 7:6 to about7:3.

Preparation of the Transdermal Delivery Patch

The composition, or matrix layer, may form part of a transdermaldelivery matrix patch. The transdermal delivery patch may be prepared bya variety of techniques.

One technique involves combining the polymer carrier and any inertcarrier components such as an anti-tacking agent and/or plasticizer witha suitable solvent (e.g. 50% water, 50% ethanol). This is combined witha dispersion comprising the biologically active compound and the mixtureof a mono-tocopheryl phosphate compound and a di-tocopheryl phosphatecompound, and is stirred until complete homogenisation is achieved. Inone embodiment, the composition may then be placed in a suitable mouldand dried. In a preferred method, the composition may be dried byheating up to about 90° C., preferably for 0.5 to 24 hours. However,formulating and/or drying may be conducted at a temperature within therange of about 30° C. to about 90° C. It has been found that formulatingand/or drying at a temperature of about 75° C. results in betterdelivery of the biologically active compound. In an alternateembodiment, the composition may be cast on a surface (e.g. a roller) andthen dried under heat.

The composition comprising a mixture of a mono-tocopheryl phosphatecompound and a di-tocopheryl phosphate compound and a polymer carrier issuitable for use as a matrix layer. The matrix layer may be a solid orsemi-solid layer.

The transdermal delivery patch usually would also comprise a backinglayer. The backing layer acts as a support or substrate for thecomposition, or matrix layer. When preparing a transdermal deliverypatch using a mould, the backing layer would be placed in the mouldbefore addition of the composition, or matrix layer.

Accordingly, the composition, or matrix layer, essentially has twosurfaces: a first surface and a second surface opposite the firstsurface, where the first surface is in contact with the backing layerand the second surface being adapted to be in diffusional contact withthe skin of a subject. The subject may be a human or animal.

Preferably, the backing layer is occlusive or impermeable to protect thecomposition, or matrix layer, from the outer environment. However, anon-occlusive backing layer could also be used, so long as the packagingof the transdermal delivery patch is fully occlusive to preventdegradation of the composition, or matrix layer. An occlusive backinglayer is preferred.

The backing layer may be of any thickness, however in the art, backinglayers typically have a thickness of about 0.0005 inches to about 0.01inches.

The transdermal delivery patch may further comprise a liner which is aremovable protective or impermeable layer, usually but not necessarilyrendered “non-stick” so as not to stick to the composition, or matrixlayer. The liner, which may also be referred to as the release liner,protects the transdermal delivery patch during storage. During use, therelease liner is to be removed.

The liner may be made from the same material as the backing layer,however it may also be a metal foil, Mylar (registered trademark),polyethylene terephthalate, siliconized polyester, fumed silica insilicone rubber, polytretrafluoroethylene, cellophane, siliconizedpaper, aluminized paper, polyvinyl chloride film, composite foils orfilms containing polyester such as polyester terephthalate, polyester oraluminized polyester, polytetrafluoroethylene, polyether block amidecopolymers, polyethylene methyl methacrylate block copolymers,polyurethanes, polyvinylidene chloride, nylon, silicone elastomers,rubber-based polyisobutylene, styrene, styrene-butadiene, andstyrene-isoprene copolymers, polyethylene, and polypropylene.

The release liner may be of any thickness, however in the art, releaseliners typically have a thickness of about 0.01 mm to about 2 mm.

The transdermal delivery patch may also comprise an adhesive layer. Theadhesive layer may be an additional layer to the composition, or matrixlayer, or may be included on the outer margin of the backing layer wherethe backing layer extends beyond the edges of the composition, or matrixlayer. Polymeric adhesives useful for transdermal patches includepolyacrylate polymers, rubber-based adhesives and polysiloxaneadhesives. These types of materials, as well as others, are described byVan Norstrand (The Handbook of Pressure Sensitive Adhesive TechnologySecond Edition 1989), which is hereby incorporated by reference.Examples of commercially available adhesives include, but are notlimited to, polyacrylate adhesives sold under the trademarks DUROTAK(registered trademark) by National Starch and Chemical Corporation,Bridgewater, N.J., as well as GELVA-MULTIPOLYMER SOLUTION (registeredtrademark) by Cytek Surface Specialties, Smyrna, Ga.

Advantages

It has surprisingly been found that biologically active compounds can beeffectively administered using a transdermal delivery patch comprising acomposition, or matrix layer, which comprises a mixture of amono-tocopheryl phosphate compound and a di-tocopheryl phosphatecompoundand a polymer carrier.

Transdermal delivery options for include, for example, topical creamsand gels, and skin patches.

Creams and gels may present difficulties with compliance and dosagecontrol, and may be considered messy or unpleasant by patients.

There are different forms of skin patches, including “reservoir” patchesand “matrix” patches. Patches may also be single- or multi-layered. A“reservoir” patch essentially has a liquid or gel compartment containingthe drug solution or suspension separated by a membrane and a layer ofadhesive. In a “matrix” patch, the drug dispersion is present in asemi-solid or solid layer, which may or may not also comprise theadhesive material.

Reservoir patches overcome some of the dosage difficulties with topicalcreams and gels, however the delivery may be uneven or inconsistent, andthere is some risk of perforation of the reservoir. An additional issuerelates to delivery of prescribed drugs which may be addictive andsubject to abuse. Gels, creams and reservoir patches provide limitedbarriers to extraction of the drug substance, whereas incorporation ofthe drug substance within a composition, or matrix layer, represents asignificant, if not almost impossible barrier to extraction of the drugsubstance.

Delivery of an active orally or by injection typically results in adelivery profile which is non-linear. Transdermal delivery provides anon-invasive way of potentially achieving sustained steady statedelivery.

Without wishing to be bound by theory, the presence of a mixture of amono-tocopheryl phosphate compound and a di-tocopheryl phosphatecompoundis considered to enhance the skin permeation of the biologicallyactive compound. It has also been found that the components of thecomposition, or matrix layer, do not formulate well together without thepresence of a mixture of a mono-tocopheryl phosphate compound and adi-tocopheryl phosphate compound. It has also been found that thepresence of a phosphate compound of tocopherol will act to reduce skinirritation caused by many the biologically active compounds.

FIGURES

The examples will be described with reference to the accompanyingfigures in which:

FIG. 1 is a schematic diagram of a transdermal delivery patch of oneembodiment of the present invention;

FIG. 2 is a graph comparing the delivery of oxycodone using atransdermal delivery patches of the present invention prepared withdifferent drying regimes;

FIG. 3 is a graph comparing the delivery of oxycodone using transdermaldelivery patches of the present invention prepared with and without aglue layer;

FIG. 4 is a graph comparing the delivery of oxycodone using transdermaldelivery patches of the present invention prepared with and without anocclusive backing layer;

FIG. 5 is a graph showing the results of pharmacokinetic testingconducted after application of transdermal delivery patches of thepresent invention;

FIG. 6 is a graph showing the results of pharmacodynamic testingconducted after application of transdermal delivery patches of thepresent invention;

FIG. 7 is a graph comparing the delivery of oxycodone using transdermaldelivery patches of the present invention comprising differentplasticisers;

FIG. 8 is a graph comparing the delivery of oxycodone using transdermaldelivery patches of the present invention comprising differentplasticisers and polymer carriers;

FIG. 9 is a graph showing the average change in blood glucose afterapplication of transdermal delivery patches of the present invention toeach of the animals; FIG. 10 is a graph showing the area under the curveof the graph of FIG. 9;

FIGS. 11 and 12 are graphs comparing the deposition in skin of twodiclofenac transdermal delivery patches; and

FIG. 13 is a graph comparing the permeation of two lidocaine transdermaldelivery patches.

EXAMPLES

Various embodiments/aspects of the present invention will now bedescribed with reference to the following non-limiting examples.

Example 1 Manufacture of Transdermal Delivery Patch

Final composition, or matrix layer Percentage by Components weight,after drying A combination of  1.1% w/w mono-(tocopheryl) phosphate anddi-(tocopheryl) phosphate in a ratio of 6:4 Oxycodone  5.5% w/w EudragitE100 (polymethyl 60.6% w/w methacrylate) Dibutyl sebacate 27.3% w/wSuccinic acid  5.5% w/wSmall Scale Laboratory Manufacturing

The components were dissolved in a solvent solution(acetone:isopropanol:ethyl alcohol 60:6.6:33.5 by % weight).

The resulting solution was then poured into individual casts (containingsuitable backing layers) at room temperature and the solvent was allowedto evaporate at 75° C. for 1.5 hours.

Large Scale Manufacturing

All composition, or matrix layer, components could be combined at asuitable temperature to produce a homogeneous molten mass. The moltenmass can then be cast on a cold surface (for example, a rotating millwith a suitable backing layer, or sheet, thereon) and allowed tosolidify. Individual transdermal delivery patches of varying sizes maythen be cut.

In both methods, the composition, or matrix layer, would be relativelythin; however, the thickness of the composition, or matrix layer, can bevaried depending on the desired properties of the transdermal deliverypatch. FIG. 1 shows an example of a transdermal delivery patch of oneembodiment of the present invention.

Example 2 Alternate Method for Manufacture of Transdermal Delivery Patch

Trandermal delivery patches were constructed by dissolving 20% w/w solidmixture of Eudragit E100 granules, dibutyl sebacate, succinic acid (thecomponents other than TPM and oxycodone in the composition, or matrixlayer, may collectively be referred to as the “polymer carrier”); acombination of mono-(tocopheryl)phosphate and di-(tocopheryl)phosphatein a ratio of 6:4 (TPM); and oxycodone base in 60:6.6:33.4acetone/isopropyl alcohol/ethyl alcohol. The mixture was thentransferred into 6 cm² circular aluminium cast-lined on the undersidewith polyester backing (1.66 mil, 3M Scotchpak™, 3M, MN) and the solventevaporated in an oven at either 45° C. overnight or 75° C. for 1.5hours. Where glue was used, the glue was DuroTak adhesive and in thisexample succinic acid was omitted from the formulation.

TABLE Composition, excipient ratios and manufacture conditions oftransdermal delivery patches Vol. Ratio Oxycodone stock Dry temp./Succinic Patch (PC:O:TPM)* (mg) (ml) time acid Glue 1 10:5:1 10 2 45° C.overnight Yes No 2 14:5:1 10 2 45° C./overnight Yes No 3 14:5:1  5 1 45°C./overnight Yes No 4 14:5:1  5 1 75° C./1.5 h Yes No 5 14:10:2  5 0.575° C./1.5 h No Yes *Refers to ratio of polymer carrier:oxycodone:TPM

Example 3 Comparative Testing for Drying Temperatures

Oxycodone transdermal delivery patches were made according to Example 1(small scale), testing the variable of the two different heatingregimes. The transdermal delivery patches were adhered to full thicknesshuman skin applied to a Franz cell with PBS as the receiver solution.Time points were taken at 18, 22, 24, 42, 44, 68 and 75 hours and thereceiver solution was tested by HPLC to determine the concentration ofoxycodone which had passed through the skin.

TABLE Parameters in the patches tested Oxy- Vol. Ratio codone stock Drytemp./ Succinic Patch (PC:O:TPM)* (mg) (ml) time acid Glue A 14:5:1 10 245° C./overnight Yes No B 14:5:1 10 2 75° C./1.5 h Yes No *Refers toratio of polymer carrier:oxycodone:TPM

The results outline in FIG. 2 show that the transdermal delivery patchmanufactured using the higher (accelerated) drying temperature hasincreased transdermal delivery properties compared with the transdermaldelivery patch manufactured with drying at a lower temperature.

Example 4 Comparative Testing to Determine Effect of an External GlueLayer

Transdermal delivery patches were manufactured and the receiver solutiontested as in Example 3, with testing time points of 0.5, 1, 3, 4 and 20hours.

TABLE Parameters in the patches tested Vol. Ratio Oxycodone stock Drytemp./ Succinic Patch (PC:O:TPM)* (mg) (ml) time acid Glue C 14:5:1 10 275° C./1.5 h Yes No D 14:5:1 10 2 75° C./1.5 h No Yes *Refers to ratioof polymer carrier:oxycodone:TPM

The results of this comparison outlined in FIG. 3 clearly demonstratethat using a transdermal delivery patch which includes an adhesive layerresults in reduced transdermal penetration of the oxycodone comparedwith the transdermal delivery patches formulated to be self-adhesive.

Example 5 Comparative Testing to Determine Effect of an OcclusiveBacking Layer Compared with No Backing Layer

The transdermal delivery patches were manufactured and the receiversolution tested as in Examples 3 and 4, at time points 1, 2, 3, 4 and 5hours.

TABLE Parameters in the patches tested Vol. Ratio Oxycodone stock Drytemp./ Occlusive Patch (PC:O:TPM)* (mg) (ml) time backing Glue E 14:5:110 2 75° C./1.5 h Yes No F 14:5:1 10 2 75° C./1.5 h No No *Refers toratio of polymer carrier:oxycodone:TPM

The results outlined in FIG. 4 clearly show that penetration of theoxycodone transdermally is far superior when an occlusive backing layeris used with the patch compared with a patch without the adhesivebacking layer.

Example 6 Pharmacokinetic Testing

This example compares plasma PK parameters using Patch Nos. 1, 2, 4 and5 from Example 2.

Transdermal delivery patches were cut from the polyester backing andadhered to the shaved and washed back of a 10-12 week old maleSprague-Dawley rat with a 6×7 cm Tegaderm HP™ (3M, MN) adhesive dressingeither with the backing layer in place or removed (see Table below).Tegaderm serves to hold the occlusive backing layer in place, or if thebacking layer is absent, holds the transdermal delivery patch itself inplace.

The day after the transdermal delivery patches were adhered to theshaved section, blood samples removed from the tail tip following ˜1 mmtip amputation at specified times. The PK parameters quantified were:

C_(max): the maximal observed plasma oxycodone concentration.

AUC₀₋₄: The area under the curve between 0 and 4 hours (the duration ofthe experiment was 4 hours) and is a measure of the total amount of drugdelivered.

The results in FIG. 5 and Table below demonstrate that the transdermaldelivery patches of the present invention in various formulations areable to effectively deliver the oxycodone to the rats as demonstrated bythe pharmacokinetic data.

TABLE Estimated pharmacokinetic parameters of rats administeredtransdermal delivery patches Oxycodone C_(max) AUC₀₋₄ Patch dose (mg/kg)Occlusive n (ng/mL) (ng · mL/min) 1 41.8 ± 0.4 No 17  93 ± 16 13681 ±2367 2 45.0 ± 2.1 Yes 9  92 ± 27 11959 ± 2910 4 21.7 ± 0.1 Yes 5 144 ±33 21637 ± 5189 5 18.1 ± 0.3 Yes 5  74 ± 29 11161 ± 4636 ‘n’ = no. ofanimals

Example 7 Pharmacodynamic Testing

Rats were prepared and dosed similar to Example 6 using Patch Nos. 1, 3and 5 from Example 2.

The day after the transdermal delivery patches were adhered to theshaved section, antinociception of the hind-paw was assessed with aplantar analgesiometer with the IR source calibrated to 190 Mu/cm².

The following PD parameters were assessed:

Maximum: The maximum time it took for the rat to remove its paw inresponse to the heat stimulus. The higher the number, the longer it tookfor the rat to respond and the deeper the oxycodone induced analgesia.

AUC: This is a measure of the total analgesia over the observationperiod as measured by the area under the curve between 0 and 4 hour, andis useful for comparing the response to different treatments.

The baseline response time is indicated in FIG. 6 at t=(−0.5 h) and t=0.

The results outlined in the Table below and FIG. 6 demonstrate thatanalgesia was effectively administered to the rats using a variety ofcompositions of the present invention.

TABLE Pharmacodynamic parameters from rats administered differenttransdermal delivery patches Oxycodone Max AUC₀₋₄ Patch dose (mg/kg) n(sec.) (sec/h) 1 41.0 ± 0.8 5 20.7 ± 3.5 57.6 ± 9.1  3 21.8 ± 0.6 5 22.3± 3.3 76.8 ± 13.1 5 21.6 ± 0.5 4 20.5 ± 2.3 64.0 ± 6.4  ‘n’ = no. ofanimals

Example 8 Alternate Plasticisers

The following formulations were prepared as outlined in Example 2.Formulation 1 was cast onto a die and Formulation 2 was cast onto aplate. The percentages below reflect the composition when the patch isdry

% w/w Formulation 1 (1% T80, dbs) Eudragit 100 60.59 DBS 26.28 Succinicacid 5.46 Oxycodone 5.56 Tocopheryl phosphate 0.67 Di-tocopherylphosphate 0.44 Tween 80 1.00 100.00 Formulation 2 (3% ML, 25% T)Eudragit 100 60.59 Transcutol 24.28 Succinic acid 5.46 Oxycodone 5.56Tocopheryl phosphate 0.67 Di-tocopheryl phosphate 0.44 Methyl laurate3.00 100.00

The transdermal delivery patches were adhered to full thickness humanskin applied to a Franz cell with PBS as the receiver solution. Timepoints were taken at 1, 2, and 4 hours and the receiver solution wastested by HPLC to determine the concentration of oxycodone which hadpassed through the skin.

The results are outlined in FIG. 7 and demonstrate that delivery ofoxycodone can be achieved using alternate plasticisers.

Example 9 Alternate Polymer Carrier

The following formulations were prepared as in Example 1, however withthe composition was cast onto a flat surface or plate instead of a die.

20% tran, 20% tran, 20% 3% ML, 1% Lau, tran, 3% 1% 1% Span 1% Span 1%,Span ML Span 20% w/w 20% w/w 20% w/w 3% w/w 1% w/w transcutol transcutoltranscutol Methyl laurate Span 80 3% w/w 1% Lauric 1% w/w DuroTak toDuroTak to Methyl laurate acid Span 80 100% w/w 100% w/w 1% w/w 1% w/wDuroTak to 5.5% w/w 5.5% w/w Span 80 Span 80 100% w/w OxycodoneOxycodone DuroTak to DuroTak to 5.5% w/w 1.1% w/w 1.1% w/w 100% w/w 100%w/w Oxycodone TPM TPM 5.5% w/w 5.5% w/w 1.1% w/w Oxycodone Oxycodone TPM1.1% w/w 1.1% w/w TPM TPM

The transdermal delivery patches were adhered to full thickness humanskin applied to a Franz cell with PBS as the receiver solution. Timepoints were taken at 1, 2, and 4 hours and the receiver solution wastested by HPLC to determine the concentration of oxycodone which hadpassed through the skin.

The results are outlined in FIG. 8 and demonstrate that oxycodone can bedelivered transdermally using an alternate polymer carrier.

Example 10 Investigation into the Pharmacodynamics of Insulin Formulatedinto Transdermal Delivery Patches

Four transdermal delivery patches of the present invention were testedagainst a positive control gel.

The table below sets out the composition of the composition, or matrixlayer, in each of the four transdermal delivery patches. Thepolyvinylpyrrolidone was found to provide the composition, or matrixlayer, with sufficient “tackiness” to avoid the need to include anyinert carrier components. The dry weight of each transdermal deliverypatch was 60 mg.

Patch TPM Polyvinylpyrrolidone Insulin 1 1.2 mg 54.8 mg 4 mg (6.67% w/w)(2% w/w) (91.33% w/w) 2 0.6 mg 55.4 mg 4 mg (6.67% w/w) (1% w/w) (92.33%w/w) 3 0.6 mg 56.4 mg 3 mg (5% w/w) (1% w/w) (94.0% w/w) 4 1.2 mg 50.8mg 8 mg (13.33% w/w) (2% w/w) (84.6% w/w)

The components of the composition, or matrix layer, were dissolved in asolvent solution (50% water, 50% ethanol). The resulting solution wasthen poured into individual casts (containing suitable backing layers)at room temperature and the solvent was allowed to evaporate at 75° C.for 1.5 hours.

300 mg of gel was used as the positive control, which comprised 2.25mg/ml insulin, 2% TPM (2:1), 30% ethanol, 1% carpobol 934 in wateradjusted to pH=4.7.

Study Design

The study was a cross-over design to test the effect of transdermaldelivery patches of the present invention compared to the gel. In thisdesign, each animal received four of the five treatments across thecourse of the study. The animals were male and 10-12 weeks of age. Eachtreatment group was 11 animals. All animals were >300 g in weight, andhad circulating glucose concentrations of >10 mmol/L in the fasted state(mean fasted glucose concentration was 21.37±0.85 mmol/L). The keyendpoint of the study was blood glucose levels during a 5-hour insulintolerance test, conducted as described below.

Streptozotocin Administration

Diabetes was induced by the administration of a single intraperitonealinjection of streptozotocin (STZ) 50 mg/kg (Sigma Chemicals) dissolvedin sodium citrate buffer (0.1 mol/L, pH 4.5) immediately before use.Rats were considered diabetic and included in the study if their bloodglucose was greater than 16 mmol/L 24 hours after the STZ injection. Inall groups blood glucose measurements were made by obtaining a spotsample from tail tipping. Animals were left for 5 days following STZadministration prior to testing.

Treatment Application 24 hours before the application of the gel andtransdermal delivery patches the animals were anaesthetised and ˜30 cm²of fur was shaved from the back, avoiding any damage to the skin thatcould enhance absorption of the formulations. The gel was applied at adose of 12 mg/cm² across the shaved area. The transdermal deliverypatches were adhered to the shaved area and protected with theapplication of a tegaderm dressing. The insulin tolerance tests wereperformed 24 hours after removing the fur. Following each treatment, theanimals were allowed to recover for 3 days before the next treatment.ITT (Insulin Tolerance Test)

Animals were fasted for 2 hours prior to the application of insulin orcontrol formulations. Spot blood samples were taken from the tail at 0,30, 60, 90, 120, 180, 240 and 300 minutes after the application of thegel and transdermal delivery patches. Blood glucose levels weredetermined at the same time points using glucose sticks (AccuChek, RocheDiagnostics).

Results

The gel and the transdermal delivery patches caused significantreductions in blood glucose concentrations in the diabetic rats (seeFIGS. 9 and 10). Blood glucose was significantly reduced (p<0.05) fromstarting values 30 min after application and remained lowered for theduration of the experiment. There was no statistically significantdifference in the reduction of blood glucose between the patches and geltested here, as demonstrated by the area under the curve (see FIG. 10).The transdermal delivery patches appear efficacious for the delivery ofinsulin, however, a transdermal delivery patch provides the manyadvantages described herein over a gel or other methods of delivery.

Example 11 Diclofenac Transdermal Delivery Patch

Diclofenac diethylamine transdermal delivery patches were preparedhaving the following composition:

  200 mg diclofenac diethylamine    20 mg TPM (8:2)   168 mg Eudragit  200 mg diclofenac diethylamine   168 mg Eudragit

The diclofenac diethylamine transdermal delivery patches had a surfacearea of 120 cm².

Manufacturing Method

The components listed in the table above were dissolved in 30 mlisopropanol:acetone mixture (1:1) at 45° C. The mixture was then castedover a 3M scotch pack, and dried for 90 minutes at 75° C.

In-vitro Testing (Diffusion)

Transdermal delivery patches were cut into circular discs (7 cm²) andplaced over rat skin. Receptor solution was 12 ml and had an effectivesurface with the skin equal to about 1.76 cm². After the duration of theexperiment, skin (about 7 cm²) was removed, the surface cleaned (excessgel) and extracted with 10 ml solvent.

Results

The results are reflected in FIGS. 11 and 12.

Diffusion Dose:  2.92 mg/1.76 cm² Skin extraction Dose: 11.78 mg/7.06cm²

Example 12 Lidocaine Transdermal Delivery Patches

Lidocaine transdermal delivery patches were prepared having thefollowing composition:

  100 mg lidocaine base    20 mg TPM (8:2)   168 mg Eudragit   100 mglidocaine base   168 mg Eudragit

The lidocaine transdermal delivery patches had a surface area of 120cm².

Manufacturing Method

The components listed in the table above were dissolved in 30 mlisopropanol:acetone mixture (1:1) at 45° C. The mixture was then castedover a 3M scotch pack, and dried for 90 minutes at 75° C.

In-vitro Testing (Diffusion)

Transdermal delivery patches were cut into circular discs (7 cm²) andplaced over rat skin. Receptor solution was 12 ml and had an effectivesurface with the skin equal to about 1.76 cm². After the duration of theexperiment, skin (about 7 cm²) was removed, the surface cleaned (excessgel) and extracted with 10 ml solvent.

Results

The results are reflected in FIG. 13.

Diffusion Dose: 1.46 mg/1.76 cm² Skin extraction Dose: 5.89 mg/7.06 cm²

In this specification, except where the context requires otherwise, thewords “comprise”, “comprises”, and “comprising” mean “include”,“includes”, and “including” respectively, i.e. when the invention isdescribed or defined as comprising specified features, variousembodiments of the same invention may also include additional features.

Although this invention has been described by example and with referenceto possible embodiment thereof, it is to be understood thatmodifications or improvements may be made thereto without departing fromthe scope of the invention.

The invention claimed is:
 1. A transdermal delivery patch for administration of a biologically active compound, the transdermal delivery patch comprising a matrix layer, wherein the matrix layer comprises: (i) a mixture of a mono-tocopheryl phosphate compound and a di-tocopheryl phosphate compound, wherein the mixture of a mono-tocopheryl phosphate compound and a di-tocopheryl phosphate compound is present in an amount of about 0.1% w/w to about 5% w/w of the total concentration of the matrix layer, and wherein the mono-tocopheryl phosphate compound and the di-tocopheryl phosphate compound are present in a ratio (% w/w) that is within a range of about 4:1 to about 1:4; (ii) a polymer carrier comprising polymers selected from the group consisting of polyacrylates, wherein the polymer carrier is present in an amount within the range of about 30% w/w to about 80% w/w of the total concentration of the matrix layer; and (iii) a biologically active compound, wherein the biologically active compound is an opioid selected from the group consisting of morphine, codeine, thebaine, hydromorphone, hydrocodone, oxycodone, dihydrohydroxycodeinone (oxycodone base), oxymorphone, desomorphine, diacetylmorphine, nicomorphine, dipropanoylmorphine, benzylmorphine and ethylmorphine, and wherein the biologically active compound is present in an amount within the range of about 0.1% w/w to about 10% w/w of the total concentration of the matrix layer.
 2. The transdermal delivery patch of claim 1, wherein the mono-tocopheryl phosphate compound is selected from the group consisting of mono-(tocopheryl) phosphate, mono-(tocopheryl) phosphate monosodium salt, mono-(tocopheryl) phosphate disodium salt, mono-(tocopheryl) phosphate monopotassium salt and mono-(tocopheryl) phosphate dipotassium salt, and the di-tocopheryl phosphate compound is selected from the group consisting of di-(tocopheryl) phosphate, di-(tocopheryl) phosphate monosodium salt and di-(tocopheryl) phosphate monopotassium salt.
 3. The transdermal delivery patch of claim 2, wherein the mono-tocopheryl phosphate compound is mono-(tocopheryl) phosphate, and the di-tocopheryl phosphate compound is di-(tocopheryl) phosphate.
 4. The transdermal delivery patch of claim 1, wherein the ratio (% w/w) of the mono-tocopheryl phosphate compound and the di-tocopheryl phosphate compound is within a range of about 6:4 to about 8:2.
 5. The transdermal delivery patch of claim 4, wherein the ratio (% w/w) of the mono-tocopheryl phosphate compound and the di-tocopheryl phosphate compound is about 6:4.
 6. The transdermal delivery patch of claim 4, wherein the ratio (% w/w) of the mono-tocopheryl phosphate compound and the di-tocopheryl phosphate compound is about 8:2.
 7. The transdermal delivery patch of claim 1, wherein the mixture of the mono-tocopheryl phosphate compound and the di-tocopheryl phosphate compound is present in an amount within a range of about 0.1% w/w to about 3% w/w of the total concentration of the matrix layer.
 8. The transdermal delivery patch of claim 7, wherein the mixture of the mono-tocopheryl phosphate compound and the di-tocopheryl phosphate compound is present in an amount within a range of about 0.1% w/w to about 2% w/w of the total concentration of the matrix layer.
 9. The transdermal delivery patch of claim 1, wherein the polymer carrier is selected from the group consisting of polyalkyl acrylates and polymethyl methacrylates.
 10. The transdermal delivery patch of claim 1, wherein the polymer carrier is present in an amount within a range of about 55% w/w to about 65% w/w of the total weight of the matrix layer.
 11. The transdermal delivery patch of claim 1, wherein the polymer carrier further comprises inert carrier components selected from the group consisting of anti-tacking agents, tackifiers, and plasticizers.
 12. The transdermal delivery patch of claim 11, wherein the polymer carrier comprises a tackifier, and the tackifier is selected from the group consisting of acrylic, N-butyl-methacrylic copolymer, acrylic methyl, acrylic 2-ethylhexyl copolymer, polyacrylic acid, methacrylic copolymer L, aminoalkylmethacrylate copolymer E, rosin esters, hydrogenated rosins, dipropylene glycol dibenzoate, mixed hydrocarbons, and acrylic copolymers.
 13. The transdermal delivery patch of claim 11, wherein the polymer carrier comprises a plasticizer, and the plasticizer is selected from the group consisting of phthalates, esters of polycarboxylic acids with linear or branched aliphatic alcohols of moderate chain length, acetylated monoglycerides, alkyl citrates, triethyl citrate (TEC), acetyl triethyl citrate (ATEC), tributyl citrate (TBC), acetyl tributyl citrate (ATBC), trioctyl citrate (TOC), acetyl trioctyl citrate (ATOC), trihexyl citrate (THC), acetyl trihexyl citrate (ATHC), butyryl trihexyl citrate (BTHC, trihexyl o-butyryl citrate), trimethyl citrate (TMC), methyl laurate, lauric acid, lauryl lactate, lauryl alcohol, alkyl sulphonic acid phenyl ester, diethylene glycol monoethyl ether, bis(2-ethylhexyl) phthalate (DEHP), diisooctyl phthalate (DIOP), bis(n-butyl)phthalate (DnBP, DBP), diisobutyl phthalate (DIBP), bis(2-ethylhexyl)adipate (DEHA), dimethyl adipate (DMAD), monomethyl adipate (MMAD), dioctyl adipate (DOA), ethyl oleate, sorbitan monooleate, glycerol monooleate, dibutyl sebacate (DBS), dibutyl maleate (DBM), diisobutyl maleate (DIBM), benzoates, epoxidized vegetable oils, tris(tromethamine), N-ethyl toluene sulfonamide (o/p ETSA), N-(2-hydroxypropyl) benzene sulfonamide (HP BSA), N-(n-butyl) benzene sulfonamide (BBSA-NBBS), tricresyl phosphate (TCP), tributyl phosphate (TBP), triethylene glycol dihexanoate (3G6, 3GH), tetraethylene glycol diheptanoate (4G7), 1,3-butyleneglycol, dipropylene glycol, PEG400, Span 80, and polyvinylpyrrolidone.
 14. The transdermal delivery patch of claim 13, wherein the plasticizer is selected from the group consisting of methyl laurate and lauryl lactate.
 15. The transdermal delivery patch of claim 11, wherein the inert carrier components are present in an amount within the range of 0.001% w/w to about 50% w/w of the total weight of the matrix layer.
 16. The transdermal delivery patch of claim 11, wherein the inert carrier components are present in an amount within the range of 0.001% w/w to about 40% w/w of the total weight of the matrix layer.
 17. The transdermal delivery patch of claim 1, wherein the matrix layer is a solid or semi-solid layer.
 18. The transdermal delivery patch of claim 1, further comprising one or more occlusive or impermeable layers, and/or one or more non-occlusive layers.
 19. The transdermal delivery patch of claim 18, comprising an impermeable or occlusive layer, wherein the impermeable or occlusive layer is a backing layer.
 20. The transdermal delivery patch of claim 18, comprising a non-occlusive layer, wherein the non-occlusive layer is a backing layer.
 21. The transdermal delivery patch of claim 18, comprising one or more impermeable layers, wherein the impermeable layer is a removable release liner.
 22. The transdermal delivery patch of claim 21, wherein the impermeable layers are made from metal foil, Mylar, polyethylene terephthalate, siliconized polyester, fumed silica in silicone rubber, polytetrafluoroethylene, cellophane, siliconized paper, aluminized paper, polyvinyl chloride film, composite foils or films containing polyester such as polyester terephthalate, polyester or aluminized polyester, polytetrafluoroethylene, polyether block amide copolymers, polyethylene methyl methacrylate block copolymers, polyurethanes, polyvinylidene chloride, nylon, silicone elastomers, rubber-based polyisobutylene, styrene, styrene-butadiene, and styrene-isoprene copolymers, polyethylene, polypropylene, or a combination thereof.
 23. The transdermal delivery patch of claim 1, wherein the patch comprises an adhesive layer.
 24. The transdermal delivery patch of claim 1, wherein the opioid is selected from the group consisting of oxymorphone, hydromorphone and oxycodone.
 25. The transdermal delivery patch of claim 24, wherein the opioid is oxymorphone.
 26. The transdermal delivery patch of claim 24, wherein the opioid is oxycodone base. 